Alterations in the p53-SOCS2 axis contribute to tumor growth in colon cancer

Abstract

Altered expression of suppressor of cytokine signaling (SOCS) is found in various tumors. However, regulation of SOCS2 by upstream molecules has yet to be clearly elucidated, particularly in tumor cells. SCOCS2 expression was examined in tumor cells transfected with an inducible p53 expression system. The impact of SOCS2 on cell proliferation was measured with in vitro assays. Inhibition of tumorigenicity by SOCS2 knockdown was assessed via a mouse model. Expression profiles were compared and genes differentially expressed were identified using four types of p53-null cells (Saos, HLK3, PC3, and H1299) and the same cells stably expressing p53. Twelve kinds of target genes were simultaneously upregulated or downregulated by p53 in three or more sets of p53-null cells. SOCS2 expression was reciprocally inhibited by inducible p53 expression in p53-null cells, even colon cancer cells. SOCS2 promoter activity was inhibited by wild type but not mutant p53. SOCS2 knockdown inhibited tumor growth in vitro and in an animal xenograph model. SOCS2 overexpression was detected in a murine model of azoxymethane/dextran sulfate sodium-induced colitis-associated colon cancer compared to mock-treated controls. SOCS2 expression was heterogeneously upregulated in some human colon cancers. Thus, SOCS2 was upregulated by p53 dysfunction and seemed to be associated with the tumorigenic potential of colon cancer.

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“…A study has demonstrated that SOCS2 was upregulated and then promote hippocampal neurogenesis and neuronal protrusive growth in vitro [20]. Meanwhile, the heterogeneously overexpression of SOCS2 was found in some colon cancers [21]. It has been suggested previously that miR-204-5p was low expressed in tumor tissues while high expressed in adjacent healthy tissues [22].…”

SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness

“…This may reflect a role of SOCS2 not only as a negative regulator of the JAK-STAT pathway, but also as a downstream target of it. Oncogenic roles of SOCS2 were also reported in other tumor entities: SOCS2 levels were elevated in colon and prostate cancer, and high SOCS2 expression was associated with a poor prognosis in the latter 23,24 . The transcription of SOCS2 was repressed by wild type p53, and it promoted proliferation, anchorage independent growth, resistance against basal and drug induced apoptosis, and tumor growth in xenograft assays in prostate and colon cancer cell lines 23–25 .…”

“…Oncogenic roles of SOCS2 were also reported in other tumor entities: SOCS2 levels were elevated in colon and prostate cancer, and high SOCS2 expression was associated with a poor prognosis in the latter 23,24 . The transcription of SOCS2 was repressed by wild type p53, and it promoted proliferation, anchorage independent growth, resistance against basal and drug induced apoptosis, and tumor growth in xenograft assays in prostate and colon cancer cell lines 23–25 . Because our data regarding Socs2 expression and growth regulatory effects of Socs2 derived from TP53 wt mice/cells and TP53 mutant human myeloid cells, we suggest that these effects are independent of p53 and TP53 mutations in AML.…”

“…SOCS2 would therefore be predicted to act as a tumor suppressor, and was indeed down-regulated in several types of solid tumors 22 . On the other hand, oncogenic roles of SOCS2 were reported, e.g., in colon and prostate cancer 23–25 . In the healthy murine hematopoietic system, Socs2 was expressed at high levels in stem cells (HSCs) and down-regulated during differentiation 26,27 .…”

CircNOL10 suppresses breast cancer progression by sponging miR-767-5p to regulate SOCS2/JAK/STAT signaling

“…However, Das et al unveiled that low levels of SOCS2 was strongly linked to disease recurrence and metastasis in clinical specimens, and SOCS2 overexpression inhibited metastatic features of prostate cancer cells [ 39 ]. Conflicting data for SOCS2 were also observed in colorectal cancer (CRC) [ 40 , 41 ]. Differences between SOCS2 mRNA and protein levels might be attributed to the active degradation of SOCS2 protein [ 42 ].…”